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Stereoselective reduction of a morphinone

a morphinone and selective reduction technology, applied in the field of chemical synthetic methods, can solve the problems of inability to attach a poly(ethylene glycol) derivative to an active agent, difficulty in achieving the effect of binding,

Active Publication Date: 2009-09-03
NEKTAR THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for making a reduced morphinone compound, which can be used to attach a water-soluble polymer to create a drug. The method involves selectively reducing the ketone group of the morphinone molecule and attaching a polymer to it. The resulting compound can be used to treat various medical conditions. The patent also describes a composition containing a mixture of different forms of the reduced morphinone compound.

Problems solved by technology

While the general benefits of PEGylation are known, attaching a poly(ethylene glycol) derivative to an active agent is often challenging and may not always be possible.
For example, difficulties can be encountered when the active agent of interest does not include a chemical functional group suitable for reaction with a polymeric reagent.
Further, to the extent that a suitable chemical functional group is present on the active agent of interest, the resulting conjugate may be insufficiently pharmacologically active as a result of the attached polymer interfering with, for example, a binding site necessary for activity of the active agent.
Malspeis et al., however, does not describe stereoselective reduction of compounds other than naltrexone.

Method used

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Examples

Experimental program
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Effect test

example 1

Preparation of Substantially Pure α-6-OH-3-MEM-O-Naloxol Using K-tri-sec-butylborohydride

[0181]

[0182]To a solution of 3-MEM-O-naloxone base (2.0 g, 4.8 mmol, preparation described in U.S. Patent Application Publication No. 2005 / 0136031) in dry tetrahydrofuran (50 mL) under an inert atmosphere at −20° C., was added a 1M solution of potassium tri-sec-butylborohydride (7.2 mL, 7.2 mmol) slowly over 15 minutes. The solution was stirred continuously at −20° C. under a nitrogen atmosphere for an additional 1.5 hours and then water (10 mL) was added slowly. The reaction mixture was stirred another 10 minutes at −20° C. and allowed to warm to room temperature. The solvent was removed under reduced pressure and the remaining residue was dissolved in CH2Cl2 (100 mL). The CH2Cl2 phase was extracted with a 0.1 N HCl / NaCl water solution (3×100 mL) and the combined aqueous extracts were washed with CH2Cl2 (1×300 mL). Sodium carbonate was added to bring the aqueous solution to pH=8. The solution w...

example 2

Preparation of Substantially Pure α-6-OH-3-MEM-O-Naloxol Using Na-tri-sec-butylborohydride

[0185]

[0186]To a solution of 3-MEM-O-naloxone base (100 mg, 0.24 mmol, preparation described in U.S. Patent Application Publication No. 2005 / 0136031) in dry tetrahydrofuran (8 mL) under an inert atmosphere at −20° C., was added a 1M solution of sodium tri-sec-butylborohydride (0.36 mL, 0.36 nmol) slowly. The solution was stirred continuously at −20° C. under a nitrogen atmosphere for an additional 1.0 hour and then water (1 μL) was added slowly. The reaction mixture was stirred another 10 minutes at −20° C. and allowed to warm to room temperature. The solvent was removed under reduced pressure and the remaining residue was dissolved in CH2Cl2 (30 mL). The CH2Cl2 phase was extracted with a 0.1 N HCl / NaCl water solution (3×30 mL) and the combined aqueous extracts were washed with CH2Cl2 (1×30 mL). Sodium carbonate was added to bring the aqueous solution to pH=8. The solution was extracted once ag...

example 3

Preparation of Substantially Pure α-6-OH-3-MEM-O-Naloxol Using Sodium Triethylborohydride

[0188]

[0189]To a solution of 3-MEM-O-naloxone base (100 mg, 0.24 mmol, preparation described in U.S. Patent Application Publication No. 2005 / 0136031) in dry tetrahydrofuran (6 mL) under an inert atmosphere at 0° C. (via an ice bath), was added a 1M solution of sodium triethylborohydride (0.36 mL, 0.36 mmol) slowly. The solution was stirred under a nitrogen atmosphere for 5.0 hours and slowly warmed to room temperature; then acetic acid (0.5 mL) was added slowly to destroy excess sodium triethylborohydride. The solvent was removed under reduced pressure and the remaining residue was dissolved in CH2Cl2 (30 mL). The CH2Cl2 phase was extracted with a 0.1 N HCl / NaCl water solution (3×30 mL) and the combined aqueous extracts were washed with CH2Cl2 (1×30 mL). Sodium carbonate was added to bring the aqueous solution to pH=8. The solution was extracted once again with CH2Cl2 (3×30 mL) and the organic e...

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Abstract

A synthetic method is provided, wherein the method comprises stereoselectively reducing a ketone of a morphinone to form a reduced morphinone and optionally covalently attaching a water soluble polymer to the reduced morphinone.

Description

FIELD OF THE INVENTION[0001]One or more embodiments of the present invention relate to, among other things, chemical synthetic methods. In addition, the invention relates to (among other things) conjugates of a water-soluble polymer and active agent, compositions comprising the same, and methods of administering a conjugate.BACKGROUND OF THE INVENTION[0002]Conceptually, PEGylation has been described as the attachment of a poly(ethylene glycol) derivative to a pharmacologically active agent to thereby form a “conjugate.” In practice, a polymeric reagent (which is a water-soluble polymer bearing a reactive functional group or an “activated” functional group) is typically reacted with an active agent of interest in order to attach or link the water-soluble polymer (either directly or through a linking moiety) to the active agent through a covalent bond. As compared to the active agent lacking attachment of the water-soluble polymer, the conjugate may possess an extended half-life in vi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C08G73/00C07D489/02
CPCC07D489/02Y02P20/55
Inventor CHENG, LINBENTLEY, MICHAEL D.
Owner NEKTAR THERAPEUTICS INC
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